Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimbin morphogenesis and pituitary development

Pitx1 is a Bicoid-related homeodomain factor that exhibits preferential exp ression in the hindlimb, as well as expression in the developing anterior p ituitary gland and first branchial arch. Here, we report that Pitx1 gene-de leted mice exhibit striking abnormalities in morphogenesis and growth of th e hindlimb, resulting in a limb that exhibits structural changes in tibia a nd fibula as well as patterning alterations in patella and proximal tarsus, to more closely resemble the corresponding forelimb structures. Deletion o f the Pitx1 locus results in decreased distal expression of the hindlimb-sp ecific marker, the T-box factor, Tbx4. On the basis of similar expression p atterns in chick, targeted misexpression of chick Pitx1 in the developing w ing bud causes the resulting limb to assume altered digit number and morpho genesis, with Tbx4 induction. We hypothesize that Pitx1 serves to criticall y modulate morphogenesis, growth, and potential patterning of a specific hi ndlimb region, serving as a component of the morphological and growth disti nctions in forelimb and hindlimb identity. Pitx1 gene-deleted mice also exh ibit reciprocal abnormalities of two ventral and one dorsal anterior pituit ary cell types, presumably on the basis of its synergistic functions with o ther transcription factors, and defects in the derivatives of the first bra nchial arch, including cleft palate, suggesting a proliferative defect in t hese organs analogous to that observed in the hindlimb.